A system for selectively delivering a drug to colon by an oral administration (hereinafter "colon selective drug delivery system") has several pharmaceutical benefits. First, the colon selective drug delivery system allows local treatment of a colonic disease, e.g., ulcerative colitis, Crohn's disease or colon cancer. Second, the colon selective drug delivery system allows lowering of the dose of a drug because the drug can directly act on the colon, thus reducing undesirable and potentially harmful side effects compared with a systemic administration.
Further, the colon selective drug delivery system is useful in administering a drug which is an irritant to the mucosa of the upper gastrointestinal tract such as the stomach or small intestine, e.g., non-steroidal anti-inflammatory agents; or a drug which is degraded by gastric juice or an enzyme present in the upper gastrointestinal tract, e.g., a peptide or protein. It was reported that the preferred targeting site of protein drugs is the colon because the concentration of a protease is significantly lower in the colon than in the stomach or small intestine (see J. Kopecek et al., Proc. Int. Symp. Control. Rel. Bioact. Material 17, 130-131, 1990).
Further, it was recently reported that the colon selective drug delivery system delays the efficacy of drug for a long time and increase the bioavailability of the drug (see A. Sintov et al., Int. J. Pharma., 143, 101-106, 1996). That is, in case of the colon selective drug delivery system, the drug resides at the colon for a longer time than at other digestion organs, and therefore, the time for drug absorption becomes prolonged and the total bioavailability of the drug increases.
A composition for selectively delivering a drug to the colon generally must meet the following four requirements: (1) the composition is not degraded or disintegrated at the upper gastrointestinal tract; (2) the composition does not release the drug loaded therein at the upper gastrointestinal tract; (3) the composition releases the drug effectively at the targeting site of the colon, e.g., the ascending colon, the transverse colon or the descending colon; and (4) the composition is easy to formulate in a form suitable for loading the drug. Further, it is preferred that the composition has a good processability.
Many studies have been made to develop such a colon selective drug delivery composition satisfying the above requirements. For example, U.S. Pat. Nos. 5,482,718; 4,627,851; 4,693,895; 4,705,515; and 4,904,474; EP 621 032 A1; JP 34929/1991 A; U.S. Pat. No. 5,536,507; EP 453 001 A1; U.S. Pat. No. 5,171,580; and EP 572 942 A2 disclose time-controlled drug compositions which are designed to prevent the drug release for a period which is expected to be sufficient for the composition to pass through the upper gastrointestinal tract. Further, U.S. Pat. Nos. 5,401,512 and 5,541,170 and WO 95/11024 describe drug compositions for selectively releasing the drug in the colon by way of exploiting the difference in pH between the colon and other digestion organs.
However, the above-mentioned compositions are not always effective in delivering the drug to the colon because the transit time and the pH in the upper gastrointestinal tract vary among individuals.
Further, there was reported a prodrug which is prepared by covalently bonding drug molecules to carrier molecules wherein the covalent bond is broken only by an enzyme produced by colonic bacteria, in order that the prodrug is degraded to release the drug only at the colon (see WO 84/04041 and WO 93/22334; A. D. McLeod et al., J. Pharm. Sci. 83, 1284-1288, 1994; D. R. Friend et al., J. Med. Chem. 27, 261-266, 1984; B. Haeberlin et al., Pharm. Res. 10, 1553-1562, 1993; D. R. Friend et al., J. Med. Chem. 28, 51-57, 1985; D. R. Friend, S.T.P. Pharma Sci. 5, 70-76, 1995; and J. P. Brown et al., J. Med. Chem. 26, 1300-1307, 1983).
However, in order to use a drug in the form of a prodrug, the drug must meet the requirements that it has at least one functional group for said covalent bonding; it is stable enough to endure the condition of a covalent bond forming reaction and the prodrug can easily revert to the drug in the colon. Due to the above limitations, it is very hard to develop a prodrug.
It is well known that enzymes capable of breaking an azo bond or various bonds in a polysaccharide are present in the colon. WO 91/16057 and EP 398 472 A2 disclose compositions containing an azo polymer having azo bonds. This technique exploits the fact that azo bonds are not degraded at the upper gastrointestinal tract, but degraded at the colon. This method has an advantage in that the composition is relatively stable at the upper gastrointestinal tract. However, it was reported that azo reductase cannot easily approach the azo bond of the azo-polymer due to the hydrophobic nature of the azo-polymer, thus resulting in slow degradation of the composition containing the azo polymer at the colon (see P. Y. Yeh et al., Macromol. Chem. Phys., 196, 2183-2202, 1995). Therefore, the composition containing the azo polymer has the critical disadvantage that release of the drug from the composition is not effective in the colon. And, a composition containing an azo polymer has a problem of safety as well.
The technique of using enzymes capable of breaking various bonds in polysaccharides are more beneficial than that of using the azo bond breaking enzyme, in terms of safety and degradability at the colon; for the most part, polysaccharides are natural polymers which are safe, biodegradable, and hydrophilic.
For example, U.S. Pat. No. 4,432,966 discloses a composition comprising microcrystalline cellulose and ethyl cellulose; EP 627 173 A1 describes a cellulose composition; WO 95/35100 discloses a starch capsule and a composition comprising an enteric coating; U.S. Pat. No. 5,422,121 suggests a composition containing a guar gum or locust bean gum blended with ethyl cellulose. However, it is difficult to form a polysaccharide film, and therefore, a polysaccharide is generally formulated together with a hydrophobic film forming material. A hydrophobic film forming material generally has a lower swelling ratio than that of a polysaccharide. Due to this difference in the swelling ratio, the film made of a polysaccharide and a film forming material may crack during the passage through the stomach and small intestine. Accordingly, in this method, the drug is released at the upper gastrointestinal tract.
On the other hand, WO 94/01136 discloses a delivery composition containing a chemically cross-linked hydrogel of dextran. However, this composition also has problems: the hydrogel swells during its passage through the upper gastrointestinal tract, releasing a major portion of the drug loaded in the composition; and when the composition reaches the colon, the composition is very slowly degraded due to the presence of strong cross-linking chemical bonds, thus rendering the drug delivery not colon selective.
Further, U.S. Pat. No. 5,505,966 discloses a pharmaceutical composition containing calcium pectinate as a major component and a filler such as pectin, dextran and/or avicel. U.S. Pat. No. 5,525,634 describes a pharmaceutical composition containing a synthetic or natural polymer which is degradable by a colonic enzyme, wherein calcium pectinate is disclosed as an example of a natural polymer.
In the '966 patent, the calcium pectinate composition is employed in the form of a coacervate pellet, but it has the disadvantage that calcium pectinate, which is insoluble in water, converts to a water soluble sodium or potassium pectinate in the course of passing through the upper gastrointestinal tract by exchanging calcium ions with sodium ions or potassium ions present in the digesting solution, and therefore, the pellets disintegrate and release the drug therefrom.
To solve the above problem, the '634 patent suggests a compressed tablet formulation which is prepared by pulverizing and compressing a pharmaceutical composition containing a drug and calcium pectinate. However, this method has various problems that the composition is difficult to pulverize and the tablet disintegrates easily in the upper gastrointestinal tract due to the high swelling property of calcium pectinate. Therefore, the compositions disclosed in both the '966 and the '634 patents depend considerably on swelling, thus on the transit time through the upper gastrointestinal tract, and not on unique characteristics of the composition.